Faculty of Medicine and Health Sciences, Department of Internal Medicine and Pediatrics (Rheumatology Unit), Ghent University, Ghent, Belgium.
Molecular Immunology and Inflammation Unit, VIB Center of Inflammatory Research, Ghent, Belgium.
Ann Rheum Dis. 2019 Jun;78(6):787-795. doi: 10.1136/annrheumdis-2018-214627. Epub 2019 Mar 30.
The mechanisms driving onset of joint inflammation in arthritides such as rheumatoid arthritis and spondyloarthritis and the conversion to disease chronicity are poorly understood. We hypothesised mechanostrain could play an instrumental role herein by engaging local and/or systemic pathways, thereby attenuating disease course and outcome.
The development of collagen antibody-induced arthritis (CAIA) in C57BL/6 mice was evaluated both clinically and histologically under different loading regimens: control, voluntary running or hindpaw unloading. Bone surface porosity was quantified by high-resolution µ-CT. Gene expression analyses were conducted by microarrays and qPCR on microdissected entheses, murine and human synovial tissues (both normal and inflamed). Serum cytokines and chemokines were measured by ELISA. The influence of complement activation and T regulatory (Treg) cell function on the induction and resolution phase of disease was studied by respectively pharmacological modulation and conditional Treg depletion.
Voluntary running strongly impacts the course of arthritis by impairing the resolution phase of CAIA, leading to more persistent inflammation and bone surface porosity. Mechanical strain induced local complement activation, increased danger-associated molecular pattern expression, activating Fcγ receptors as well as changes in fibroblast phenotype. Interestingly, complement C5a receptor blockade inhibited the enhanced joint pathology caused by voluntary running. Moreover, Treg depletion led to a loss of disease resolution in CAIA mice, which was not observed under voluntary running conditions.
Running promotes onset and chronicity of arthritis by local upregulation of complement activators and hampering regulatory T cell feedback loops.
类风湿关节炎和脊柱关节炎等关节炎中关节炎症发作和向慢性疾病转化的机制尚未完全清楚。我们假设机械应变可能在此过程中发挥重要作用，通过激活局部和/或全身途径，从而减轻疾病的进程和结果。
在不同的加载方案下（对照、自愿跑步或后肢去负荷），评估 C57BL/6 小鼠胶原抗体诱导性关节炎（CAIA）的临床和组织学发展。通过高分辨率µ-CT 对骨表面孔隙率进行量化。通过微阵列和 qPCR 对微解剖的附接处、鼠和人滑膜组织（正常和炎症）进行基因表达分析。通过 ELISA 测量血清细胞因子和趋化因子。通过分别进行药理学调节和条件性 Treg 耗竭，研究补体激活和 T 调节（Treg）细胞功能对疾病诱导和缓解阶段的影响。
自愿跑步强烈影响关节炎的进程，通过损害 CAIA 的缓解阶段，导致更持续的炎症和骨表面孔隙率。机械应变诱导局部补体激活，增加危险相关分子模式的表达，激活 Fcγ 受体以及成纤维细胞表型的改变。有趣的是，补体 C5a 受体阻断抑制了自愿跑步引起的增强关节病理。此外，在 CAIA 小鼠中耗尽 Treg 会导致疾病缓解的丧失，而在自愿跑步条件下则没有观察到这种情况。
跑步通过局部上调补体激活物和阻碍调节性 T 细胞反馈环促进关节炎的发作和慢性化。
